The present invention, in some embodiments thereof, relates to novel compositions, unit dosage forms, articles of manufacturing and methods of repairing bone defects and, more particularly, to bone graft compositions that are characterized by controlled, pre-determined setting, curing and bio-resorbability rates and hence can be beneficially utilized for repairing bone defects. The invention also relates to an applicator particularly useful for preparing and applying bone graft compositions.
The rapid development of surgery allows carrying out bones and joints operations such as, for example, orthopedics or maxillofacial surgery including surgical removal of cysts, foci of suppuration and malignant bone tumors. These medical procedures often results in voids, gaps and other bone defects. Other examples of bone defects include those resulting, for example, from compression fractures, high-energy trauma, peri-articular fractures, cranial-maxillo facial fractures, osteoporotic reinforcement (i.e. screw augmentation) and periodontal reconstruction.
Dentistry is an exemplary field in which repairing bone defects is necessary in addition to dental implants, for replacing missing teeth. When a person experiences teeth loss due to trauma or other circumstances, or suffers from periodontal disease, loss of interproximal crestal alveolar bone is one of the conditions which the practitioner must deal with. This bone loss may further result in the loss of a person's interproximal or papillary oral tissue between the corresponding teeth and may cause a bone defect that is very unappealing aesthetically, as well as difficult to restore. Without the proper regeneration of this bone defect, any replacement tooth is likely to be mal-positioned, out of proportion, shape and form, and lack interproximal tissue for a natural appearance.
Depending on the cause and/or location of the various possible bone defects within the body, the volume of the defect can vary, but may, in some cases, reach more than 6 cubic centimeters
Since natural bone healing is limited to small cavities and spans long time periods in terms of daily activity, larger bone defects often need to be filled by bone replacement materials which act as temporary fillers, offering a lattice or scaffold upon which natural bone is slowly built. These materials may be liquid, pasty or solid, and are mostly classified by their source: natural or artificial, a feature which invariably influences the biocompatibility of these materials.
Natural bone replacement materials, known as transplants or grafts, include endogenous or exogenous bone fragments. In endogenous bone grafting (autograft), the graft is harvested from a “donor site” in the patient's own body. Autografts are generally the best grafting technique and usually result in the greatest regeneration of missing bone, since the bone is 100% compatible with the patient's body. Although endogenous bone material is highly valuable due to its osteogenic (bone forming), osteoconductive (providing an inert scaffold on which osseous tissue can regenerate bone), and osteoinductive (stimulating cells to undergo phenotypic conversion to osteoprogenitor cell types capable of formation of bone) properties, it is only available in very limited amounts, and thus several surgical procedures are usually necessary to obtain the necessary bone mass from several donor sites. These repetitive surgical procedures pose severe disadvantages to this otherwise beneficial technique.
Exogenous bone graft may be derived from either a human donor (allograft), after undergoing rigorous tests and sterilization, or from an animal source (xenograft), most commonly bovine, after being specially processed to make it biocompatible and sterile. In both cases the exogenous bone acts as a “filler” until the patient's body replaces it with its own natural bone. Unfortunately, exogenous grafts have low or no osteogenicity, increased immunogenicity and a much faster resorption compared to autogenous bone. In clinical practice, fresh allografts are rarely used because of immune response and the risk of transmission of disease. The frozen and freeze-dried types are osteoconductive but are considered to be only weakly osteoinductive at best. Freeze-drying diminishes the structural strength of the exogenous graft and renders it unsuitable for use in situations in which structural support is required. In practice, exogenous bone transplant is often not successful.
Some of the most significant advances in biomaterial research over the last 30 years have been in the field of bone graft substitutes, also termed synthetic grafts or alloplastic grafts, which use inert, man-made synthetic materials that mimic natural bone. Examples of synthetic bone implant and/or bone filler materials include, but are not limited to, metals (for example, special steels, noble metals, platinum or titanium, often used in the replacement of joints) ceramic materials (for example, alumina, glass-ceramics or hydroxylapatite ceramics), calcium phosphate, calcium sulfate and more.
While natural bone grafts are preferable in terms of biocompatibility, they are less practical, especially in the treatment of large cavities, and using synthetic grafts may in fact avoid the additional surgical operations needed to obtain enough natural bone mass.
The type of the synthetic bone replacement material of choice is often dictated by the size, type and location of the bone cavity.
Resorbable bone replacement materials (otherwise termed biodegradable, bioerodable, or bioabsorbable) include materials that are broken down and gradually absorbed or eliminated by various processes in the body. These materials are used as temporary support media or as osteoconductive bone grafts, temporarily filling bone cavities and allowing the body itself to compensate, in the course of time, the defect with living bone material. The exact degree of resorbability is preferably selected such that the rate of resorption at the recipient bone site will match the rate of natural bone growth.
Non-resorbable bone replacement materials are used in bone implantation or “bone augmentation” when the bone cavity is too large to be ever replaced naturally, for example following surgical operations, or when replacing lost teeth. These bone implants must themselves be secured to a supporting bone. Occasionally, the use of non-resorbable bone replacement materials has to be supplemented by the use of resorbable bone replacement materials. For example, in dentistry, when the loss of teeth or periodontal disease results in the loss of the root bone, the potential dental implant site in the upper or lower jaw does not offer enough bone volume or quantity to support the dental implant. Hence, before the placement of bridges or, more commonly, dental implants, supporting bone and/or tissue must be re-grown. This procedure, known as Guided Bone Regeneration (GBR), is accomplished using bone grafts and biocompatible membranes that prevent tissue growth on or around the implant. A bone graft normally takes at least four to six months to heal, before a dental implant can be placed thereon or therein.
One of the most common substances utilized in repairing bone defects in general, and in dental applications, in particular, is hydroxylapatite (HA), Ca5(PO4)3(OH) or Ca10(PO4)6(OH)2. Hydroxylapatite is a mineral component found in bones and teeth, and is therefore characterized by the required biocompatibility. Hydroxylapatite, however, often causes irritation of the surrounding bone material. HA, having an approximate resorption time period of 18-36 months is used as a compromise between a highly resorbable and a poorly resorbable material.
Gypsum, for example, is a very soft mineral composed of calcium sulfate dihydrate, CaSO4.2H2O. This form is referred to in the art as calcium sulfate. Heating gypsum at above approximately 150° C. partially dehydrates it to obtain calcium sulfate hemihydrate, CaSO4.½H2O, is a substance in which the molecular ratio of water molecules to anhydrous calcium sulfate is 1:2, commonly known as “calcined gypsum” or “Plaster of Paris”. When calcium hemihydrate is mixed with water at ambient temperatures, it crystallizes into a strong gypsum crystal lattice in an exothermic reaction. Gypsum also has an anhydrous form, termed anhydrous calcium sulfate or calcium sulfate anhydrate, CaSO4, which is produced by further heating of the calcium sulfate hemihydrate to above approximately 180° C. Anhydrous calcium sulfate reacts slowly with water to return to the dihydrate form.
In a pure water system, the solubility of these different types of calcium sulfate ranges from about 1.0×10−2 M to about 4.0×10-2 M (at 25° C.). The anhydrate form, however, is a very hard crystal (hardness rating of 3.5, according to the Mohs Hardness Scale, and a relative density of about 3.0, and has an extremely low dissolution rate in water, even when finely ground, rendering it impractical for in vivo applications. In practice, the anhydrate form is mainly used as a desiccant.
Calcium sulfate compositions are also widely used in bone treatment, and in GBR procedures. Calcium sulfate was first used by Dreesman to obliterate bone cavities caused by tuberculosis in 1893. In 1959, Peltier became the first American to report on the use of calcium sulfate as a bone-graft substitute. The strong crystal structure obtained upon a reaction of the calcium sulfate hemihydrate with water renders it highly suitable for casting into sheets, sticks and molds. This feature attributes to its wide spread use in various applications such as setting broken bones (see, for example, U.S. Pat. No. 3,746,680), in dental GBR for filling small volume cavities (see, for example, U.S. Pat. No. 6,224,635) or in the preparation of dental molds (see, for example, U.S. Pat. No. 4,526,619). Combined with natural or synthetic polymers, calcium sulfate hemihydrate is used for the controlled release of medicaments or pesticides (see, for example, U.S. Pat. No. 6,030,636) or as an implant having a controlled resorption rate in vivo for stimulating bone growth (see, for example, U.S. Patent Application No. 2004/0254259, and U.S. Pat. Nos. 4,192,021 and 4,381,947). In addition, U.S. Patent application Nos. 20020110541, 20020071827 and 20030050710, and U.S. Pat. Nos. 7,371,408, 7,371,409 and 7,371,410, teach bone graft substitute compositions based on various forms of calcium sulfate.
U.S. Pat. No. 6,224,635 teaches that when calcium sulfate hemihydrate dissolves in vivo it elevates the local calcium ion concentration in the surrounding tissue. Then, the newly formed calcium ions react with body fluids to cause local precipitation of calcium phosphate bone mineral in the new soft granulation tissue that is formed around the calcium sulfate as it dissolves and recedes. Since the calcium phosphate is stable in vivo, it provides a matrix for the formation of new in-growing bone tissue, although this process is quite unpredictable.
Unfortunately, the calcium sulfate hemihydrate form is not suitable for the treatment of large cavities due to its expansion properties during setting, which cause pain to the patients. Furthermore, it is characterized by a high dissolution rate and inherently by a fast resorption by the human bone, usually within two to seven weeks, depending upon the particular surgical site. Such a fast absorption renders the calcium sulfate hemihydrate impractical for use in the treatment of large bone cavities, since it cannot be retained at the bone site for long periods of time and is resorbed faster than it can be replaced by new bone, thereby reducing its value to both patient and practitioners in fields such as orthopedics or maxiofacial surgery [ArunK. Garg, D. M. D in Bones biology, Harvesting, Grafting for dental implant. Quintessence publication Ed-1].
The calcium sulfate dihydrate form has acceptable expansion properties. However, its use in repairing bone defects is limited since it has no cementitious properties. Thus, while calcium sulfate dihydrate is often used as surgical cement, additional components are often required so as to achieve the desired cementitious effect. U.S. Pat. No. 5,281,265, for example, teaches that a calcium ion can react with a citrate ion to form a less soluble calcium citrate salt, thus forming cement. Hence, while calcium sulfate dihydrate can theoretically fill large bone cavities, the obtained structures are not stable and invariably break. In fact, there is only limited practical healing success when using calcium sulfate dihydrate in the treatment of large bone defects.
Clearly, the use of the currently available biocompatible synthetic compositions for filling large bone cavities suffer severe disadvantages, such as irritation of the surrounding bone material, poor resorbability, low stability and high expansion, which result in pain and discomfort to the patient and a possible leaking out of the filling material or even a loss of the implant.
WO 2007/046109, of which one of the present inventors is a co-inventor, and which is incorporated by reference as if fully set forth herein, teaches bone grafting compositions which comprise flakes made of a mixture CSH and CSD, which exhibit both the cementitious and binding properties of CSH and the strength and longer resorption period of the rigid CSD and tricalcium phosphate (TCP) granules.
WO 2000/045734 describes a composite, which can be used for filling in bone voids, and which comprise various forms of calcium sulfate hemihydrate, calcium sulfate dihydrate, or combinations thereof.
U.S. Pat. No. 5,281,265 discloses a bone cement material comprising calcium sulfate components, wherein the interaction of a calcium-containing cementing component and a setting component produces a calcium-containing cement which has reduced solubility in water relative to the calcium-containing cementing component. Useful cementing components taught therein are calcium sulfate dihydrate, calcium sulfate hemihydrate and anhydrous calcium sulfate. The cement taught therein can be dried after its preparation, and broken into particles, to form suitable sized particles such as granules.
WO 2000/027316 refers to surgical cement, composed mainly of a calcium sulfate salt, for example calcium sulfate dihydrate, calcium sulfate hemihydrate, anhydrous calcium sulfate and mixtures thereof. The cement taught therein can be used in combination with an implant to repair a bone defect. U.S. Patent Application No. 2003/167093 relates to a bone replacement material based on combination of calcium phosphate compounds, comprising at least two fillers with different in vivo dissolution rates, wherein the compound with the higher dissolution rate will dissolve and create pores for bony ingrowth, and whereas the compound with the lower dissolution rate will still provide strength and toughness reinforcement to the composition, and will only dissolve at a later stage, when more bony material has been formed to support the bone structure, to create additional pores.
WO 2008/094585 provides a method for facilitating bone repair by providing calcium sulfate hemihydrate particles, wherein at least 50% of the particles have a diameter of 50 to 500 nanometer, mixing the particles with an aqueous solution to obtain a paste, applying the paste to an area of bone in need of repair, and allowing the paste to set.